SPECIAL CONTRIBUTION aspirin, myocardial infarction; beta-blockers, myocardial infarction; calcium channel blockers; lidocaine, myocardial infarction; myocardial infarction; nitrates, myocardial infarction
The Golden Hours of the Myocardial Infarction: Nonthrombolytic Interventions Emergency care of patients with acute myocardial infarction requires active decision making to use agents that may improve morbidity and mortality. Thrombolysis remains the primary tool to accomplish this goal. Other pharmacologic agents, including lidocaine, nitrates, calcium channel blockers, f~-blockers, and aspirin, have been used acutely in myocardial infarction in the hopes of preventing death and salvaging myocardium. The decision to select one or all of these agents requires a knowledge of the clinical evidence of their efficacy and risk-to-benefit ratios. The clinical studies of the use of these agents acutely in the management of myocardial infarction are reviewed. [Mitchell JM, Wheeler WS: The golden hours of the myocardial infarction: Nonthrombolytic interventions. Ann Emerg Med May 1991;20:540-548.] INTRODUCTION Because of the reassessment of lidocaine, the advent of thrombolytic and aggressive reperfusion therapy, and newer data on the usefulness of other agents, especially aspirin and p-blockers, the management of acute myocardial infarction has changed significantly in the past decade. Previous management was directed at reduction of infarct extension and the prevention and treatment of arrhythmic deaths. This consisted mainly of bedrest, oxygen, pain relief, prophylactic antiarrhythmics, and treatment of complications. Now, in addition to previous directives, the goal in myocardial infarction therapy is preservation of myocardium in an attempt to improve mortality as well as postinfarction lifestyle and morbidity. Although reperfusion holds the most promise in myocardial salvage, studies continue to search for adjunct agents that may decrease myocardial oxygen demand as well as infarct size. Other agents studied in myocardial infarction management include prophylactic lidocaine, nitrates, calcium channel blockers, f~-blocking agents, and aspirin. This article presents an overview of the clinical studies of the use of these agents acutely in myocardial infarction and determines guidelines for their use. Trials from a literature search of the past seven years as well as older landmark studies are included.
Joyce M Mitchell, MD, FACEP* William S Wheeler, MD, FACCt Greenville, North Carolina From the Departments of Emergency Medicine* and Medicine,t East Carolina University School of Medicine/Pitt County Memorial Hospital, Greenville, North Carolina.
Received for publication March 12, 1990. Revision received October 12, 1990. Accepted for publication December 18, 1990. Presented at the Winter Symposium of the American College of Emergency Physicians in Tucson, Arizona, March 1990. Address for reprints: Joyce M Mitchell, MD, FACER Department of Emergency Medicine, East Carolina University School of Medicine/Pitt County Memorial Hospital, Greenville, North Carolina 27858-4354.
LIDOCAINE Initially synthesized and used as a local anesthetic in 1943, lidocaine demonstrated suppressive effects on ventricular premature beats (VPBs) during studies of the hemodynamic effects of its IV administration in the 1950s. 1 With the development of coronary care units in the 1960s, the prevention of ventricular fibrillation was advocated by Lown et al, 2 who also promoted the concept of warning arrhythmias that heralded the onset of ventricular fibrillation. Lidocaine was therefore administered when warning arrhythmias occurred. The theory of warning arrhythmias, however, was not supported in further studies. Ventricular fibrillation did not occur in all patients with warning arrhythmias and did occur in their absence, g-6 It was at this time that truly prophylactic use of lidocaine began. Lidocaine was administered to patients with suspected myocardial infarction before the recognition of ventricular ectopy or arrhythmias. The concept of prophylactic lidocaine is controversial. It has been adamantly advocated by some and highly questioned by others. The rationale
20:5 May 1991
Annals of Emergency Medicine
540/97
M Y O C A R D I A L INFARCTION Mitchell & Wheeler
TABLE 1. Lidocaine in acute myocardial infarction
Reference
Year
Setting
Lie et al lo
1974
Hospital
Barnaby et alit Koster and Dunningr2
1983 1985
Hospital Prehospital
Dunn et a113
1985
Varied
No. of Patients Treated Placebo Total
Route
Dose (mg)
Infusion (mg/min)
Treatment or Study Period (br)
107
105
212
IV
100
3
48
111 2,987
... 3,037
111 6,024
IV IM
75 400
4.-~.2
48 1
207
195
402
IM IV
300 100
1
End Points VF, VPBs, mortality VE VT, VPBs VE mortality VE mortality
VF, venbieular fibrillation; VPBs, ventbcular premature beats; ~ ventrieular lachycardia.
for its use should be based on four basic assumptions, which are disCussed: 1) primary ventricular fibrillation is common in myocardial infarction, 2) the occurrence of ventricular fibrillation increases mortality, 3] lidocaine prevents p r i m a r y ventricular fibrillation and improves mortality, and 4) the benefits of lidocaine outweigh its adverse effects. Based on the clinical trials reported, the use of prophylactic lidocaine in all patients with suspected myocardial infarction is not supported. 7 First, studies have demonstrated a 3% to 10% in-hospital occurrence of primary ventricular fibrillation in association with m y o c a r d i a l infarction. s-lo Many sudden deaths occur outside of the hospital, and the incidence of ventricular fibrillation is inversely related to the time of onset of chest pain. lo Second, this has been suggested by several studies of in-hospital mortality of patients with primary ventricular fibrillation. An average of 19% of those with primary ventricular fibrillation died compared with an average of 8% in patients without primary ventricular fibrillation. 1 These n u m b e r s do not i n c l u d e p a t i e n t s with secondary ventricular fibrillation associated with congestive heart failure. This suggests that prevention of ventricular fibrillation would have a favorable effect on outcome in patients with myocardial infarction. Third, animal studies have shown mixed results on the effects of lidocaine in the suppression of ventricular a r r h y t h m i a s . Several clinical studies have assessed the efficacy of prophylactic lidocaine in preventing ventricular fibrillation in acute myocardial infarction. The characteristics of these trials are outlined (Table 1). Lie et al studied 212 patients with documented myocardial infarction. H 98/541
P a t i e n t s were excluded from the study if they were more than 70 years old or had congestive heart failure, shock, complete atrioventricular block, bradycardia, or persistent ventricular tachycardia or ventricular fibrillation on admission. None of the treated patients developed ventricular fibrillation. Of the placebo group, nine developed ventricular fibrillation; this was a statistically significant difference and supported the ass u m p t i o n that lidocaine prevents ventricular fibrillation. All but one of the nine were successfully defibrillated. In four of nine patients who developed ventricular fibrillation warning arrhythmias did not occur, suggesting that warning arrhythmias were not helpful in the decision to administer lidocaine. The mortality rates in both groups were the same. Barnaby et al treated all patients in their study with lidocaine within 24 hours of the onset of acute myocardial infarction. 1~ Exclusion criteria were similar to those in Lie et al's study. No patients developed ventricular fibrillation. Thirty-two percent had warning arrhythmias, and 4% had n o n s u s t a i n e d ventricular tachycardia. Four developed hypotension, and one developed bradycardia. Thirty percent of patients suffered symptoms of lidocaine toxicity, none of which was major. Despite the fact that this was an uncontrolled study, the investigators made the conclusion that prophylactic lidocaine was efficacious in suppression of ventricular fibrillation and that its use was particularly important outside the coronary care unit where close monitoring and rapid defibrillation were less available. In 1985, Koster and Dunning studied the use of prophylactic IM lidocaine in prehospital-care patients with suspected myocardial infarcAnnals of Emergency Medicine
tion.13 All patients were admitted to the study based on symptoms regardless of age, with exclusions for severe congestive heart failure, pretreatment with lidocaine, and resuscitation from ventricular fibrillation or by a physician's judgment. Of the patients included in the study, myocardial infarction was documented in 1,935. The IM route was selected because of its ease of use in the prehospital phase; it had been demonstrated previously to produce therapeutic serum levels 15 minutes after injection. Ventricular fibrillation was treated by defibrillation. The study period was one hour. During this time, eight of the treated and 17 of the untreated patients developed ventricular fibrillation (P = NS). However, in the last 45 minutes of the study, two of the lidocaine-treated and 12 of the untreated patients developed ventricular fibrillation, which was statistically significant. Ventricular fib r i l l a t i o n was d e f i b r i l l a t e d succ e s s f u l l y in all b u t one of t h e patients, in whom it was unrecognized and untreated for 11 minutes. The m o r t a l i t y rates in patients who developed ventricular fibrillation were virtually the same in both groups. More patients treated with ]idocaine developed asystole, but asystolic deaths in both groups were the same. The total mortality for both groups was also essentially the same. The authors concluded that if ventricular fibrillation had not been treated, by defibrillation, the administ r a t i o n of l i d o c a i n e w o u l d have caused a 31% reduction in mortality. Therefore, prophylactic IM ]idocaine would be useful in the setting in which potential sudden death is possible and immediate defibrillation is not available. Finally, Dunn et al studied the effects of lidocaine in patients with 20:5 May 1991
MYOCARDIAL INFARCTION Mitchell & Wheeler
TABLE 2. IV nitroglycerin in acute myocardial infarction
Reference Bussman et al2o
No. of Patients Year Treated Placebo Total Time*
Duration of Study (hr)
1981
31
29
60
Varied
48
Jaffe et a117 Flaherty et al2~
1983 1983
43 56
42 48
85 104
Within 10 hr Within 12 hr
? 24 Varied
Korewicki et a122
1984
39
38
77
Within 8 hr
48
End Points Infarct size (OK, CK-M8) infarct size (CK) Infarct extension, new heart failure, arrhythmias, infarct size, mortality Infarct size (OK), hemodynamics
*Onsel of symptoms to initiation of therapy
suspected myocardial infarction. 14 These patients were treated in the prehospital phase (78%), in the emergency department (18%), or after admission (4%) with similar exclusion criteria as previous studies. Of the patients studied, 364 had either myocardial infarction or acute coronary insufficiency. During the study period, three untreated patients developed v e n t r i c u l a r fibrillation (P = NS), and three lidocaine-treated patients developed sustained ventricular tachycardia (P = NS). More patients treated with lidocaine developed 2:1 atrioventricular block or asystole with death, but this.was not statistically significant. The mortality outside the study period was the same in both groups. Although the authors stated that their study may have been too small to create statistically significant differences in the two groups, they concluded that prophylactic lidocaine should not be advocated as the routine practice in acute myocardial infarction. Fourth, Rademaker et al studied adverse side effects in patients who received prophylactic lidocaine (100 mg IV followed by a 3 mg/min infusion) compared with those who did not. is T h e y f o u n d t h a t lidocaine caused significantly more side effects, albeit minor in m a n y cases, and that they were more common in patients without myocardial infarction. Five of 145 patients suffered life-threatening side effects, including seizures, coma with respiratory arrest, and persistent severe sinus bradycardia. They concluded that the adverse effects of lidocaine may negate its routine prophylactic use. Yusuf et al pooled the results of 11 randomized trials of 8,527 patients, which showed that lidocaine reduced 20:5 May 1991
the risk of ventricular fibrillation by 36% with a c o n c o m i t a n t but only borderline statistically significant doubling of fatal asystole. 16 They concluded that the routine use of antiarrhythmics in asymptomatic patients was not supported by pooled data. These studies suggest that lidocaine is effective in preventing primary ventricular fibrillation, but the mortality in treated versus untreated patients was the same. 11d4 Recently, Hines et al performed a meta-analysis of the studies on prophylactic lidocaine, supporting this finding. 7 They also showed that monitored patients with uncomplicated myocardial infarction were more likely to die during the treatment period if they received the drug. Despite potential psychological and physical consequences of resuscitation from ventricular fibrillation, the adverse effects of lidocaine probably outweigh its routine use due to the negative mortality effect and the potential of life-threatening side effects in patients who are suspected but later disproved of suffering acute myocardial infarction. The conclusion of Koster and Dunning is probably a good guideline for the use of prophylactic lidocaine: When defibrillation is unavailable and potential ventricular fibrillation is possible, prophylactic lidocaine may improve mortality. 13 With the development of emergency medical technician-defibrillation status, the need for this in the prehospital phase of management of patients with suspected myocardial infarction might be eliminated.
NITRATES Nitrates have been used since the Annals of Emergency Medicine
latter part of the 1800s for chest pain syndromes but were previously considered inappropriate for use in acute myocardial infarction because of potential side effects. These adverse effects include hypotension and reflex tachycardia, which in turn would increase myocardial oxygen consumption as well as the i d i o s y n c r a t i c b r a d y c a r d i c / h y p o t e n s i v e response seen in some patients. 17 Theoretically, however, nitrates should have beneficial effects because of two main actions. First, preload and afterload reductions result in decreased left ventricular filling pressures, thus decreasing myocardial oxygen demands. In experimental studies, nitrates have been shown during acute coronary occlusion to increase collateral blood flow to ischemic areas with a secondary potential benefit on infarct size. is There have been several trials addressing the effects of nitrates on myocardial infarction. Current recommendations advocate the use of nitrates in selected patients. In 1976, Awan et al administered 0.4 mg nitroglycerin sublingually to 11 patients with documented acute m y o c a r d i a l infarction.I9 Patients were not included in this small study if they were hypotensive or demonstrated conduction disturbances, persistent arrhythmias, heart failure, or pericarditis. Infarct size was determined by precordial mapping of ST segments and was found to be decreased by sublingual nitroglycerin. This led to further studies using IV nitroglycerin because it was more titratable and side effects could be avoided. The characteristics of these studies are outlined (Table 2). Bussman et al studied patients with acute myocardial infarction documented by clinical, ECG, and enzyme criteria. ~° All patients received SwanGanz catheterization and were included in the study only if pulmonary arterial diastolic or capillary pressures were more than 15 m m Hg. Infarct size was determined by creatine kinase (CK), CK-MB, and peaks of each. The groups were also subgrouped into early (within eight hours; mean, 4.5 hours) and late (after eight hours; mean, 12.8 hours) treatment. The results demonstrated significant reduction in infarct size with nitroglycerin in both early and late treatment groups, although early treatment was associated with better 542/99
M Y O C A R D I A L INFARCTION Mitchell & Wheeler
TABLE 3. Nifedipme in acute myocardial infarction No. of Patients Initial Dose Treated Placebo Total mg Route Time (hr)*
Reference
Year
Muller et a127
1984
82
89
171
20
0ral
Sirnes et a128
1984
112
115
227
10
0ral
Wilcox et a129 (Trent trial)
1986
2240
' 2,251
4,491
10
Sublingual
Branagan et al3o
1986
46
52
98
10
Sublingual
Gottlieb et a131
1988
64
68
132
10
Walker et a132
1988
217
217
434
10
?
Sublingual
Subsequent Doses
Duration
End Points
(Within 6) 4.6+1 (Within 12) 5.5 +_ 2.9 (Within 4): 32% (8): 68% (12): 81% (Within 6) 3.3 z 0.2
Every 4 hr
14 days
Threatened MIAMI, infarct size (CK-MB), mortality Infarct size (CK-MB), mortality Mortality
(Within 12) 8.0% = 02
Repeat every hr for 2, 6 weeks then 10-30 mg every 6 hr Every 4 hr for 24 hr orally, 48 hours every 4 hr for 24 hr
(Within 6) 2.3
Repeat 10 m, 5 times daily 6 weeks for 2 days, 4 times daily Repeat 4 hr every 6 hr Approximately 28 days Repeat 4 hr, orally every 6 hr
3 days
Infarct size (CK-MB), threatened MIAMI, mortality Infarct size (CK, echocardiogram, nuclear scans) Infarct size (CK, CK-MB, others)
*Onset of symptoms to first dose MI, myocardial infarction. (), inclusion criteria
results. The study group, however, was small. Jaffe et al studied the effect and safety of IV nitroglycerin in patients with documented myocardial infarction. 17 Patients were excluded for cardiogenic shock, severe heart failure with tachycardia, and severe hypertension. Before r a n d o m i z a t i o n , the patients were classified according to site of infarct. Infarct size was measured by CK gram equivalents per meter squared. There was a borderline significant reduction in infarct size for all patients. Nitroglycerin showed a significant reduction in infarct size among patients with inferior myocardial infarctions, a positive but not statistically significant trend in subendocardia] myocardial infarctions, and no change in anterior wall myocardial infarctions. M o r p h i n e r e q u i r e m e n t s were the same in patients regardless of treatment or infarct location. Six patients developed transient laypotension w i t h o u t deleterious effects. T h e y concluded that IV nitroglycerin was safe and effective in the reduction of infarct size in patients with inferior myocardial infarctions. Flaherty et al studied the effects of IV nitroglycerin on the clinical parameters of infarct extension, new heart failure, ventricular arrhythmias, and early death as well as laboratory parameters of infarct size (thallium perfusion scans, gated cardiac blood pool scans, two-dimensional echocardiography, precordial 100/543
E C G m a p p i n g , and serial CK). 21 N i n e t y - s e v e n p a t i e n t s had docum e n t e d myocardial infarction. Patients were excluded for age of more than 75 years, hypotension, bradycardia, and severe hypertension. At the end of their study, no difference in clinical or laboratory parameters could be determined. By retrospective subgrouping of patients into groups treated less or more than ten hours after onset of symptoms, they were able to determine some difference. Individually considered, nitroglycerin did not affect the clinical complications of myocardial infarction, but early treatment with nitroglycerin significantly reduced the combination of death, infarct extension, heart failure, and ventricular arrhythmias. The three-month mortality was improved in the early nitrog l y c e r i n g r o u p (P = NS). CK p a r a m e t e r s were not affected, but there appeared to be improvement in ejection fraction measurements with early nitroglycerin treatment. Flaherty et al also recommended that the data be interpreted with caution because of the size and retrospective subgroup analysis and proposed that recommended routine nitroglycerin in acute myocardial infarction await larger trials. 21 Korewicki et al demonstrated reduction in CK parameters if the drug was administered within eight hours. 22 Other studies have refuted the preferential reduction of infarct size in inferior myocardial.infarcAnnals of Emergency Medicine
tions demonstrated by Jaffe, 23 but two studies demonstrated improvement in patients with anterior myocardial infarctions.24, 25 It is difficult to m a k e definitive conclusions about the routine use of nitrates acutely in myocardial infarction based on the data of individual studies. Pooling of results suggests that IV nitrates improve m o r t a l i t y and m a y reduce infarct size.t6,18, 26 This positive trend and the fact that IV nitroglycerin is relatively safe, with adverse effects that are usually easily managed, suggest that nitrates should be used acutely in myocardial infarction in selected patients, especially those w i t h p e r s i s t e n t chest pain. After screening patients who may be susceptible to its hypotensive effects, those who are hypovolemic or may require high filling pressures to maintain cardiac output such as right ventricular infarction, IV nitrog l y c e r i n can r e a s o n a b l y be used safely. The advocation of routine use, however, should probably await larger studies. CALCIUM CHANNEL BLOCKERS
Since their introduction, calcium channel blockers have been used for a variety of cardiovascular diseases. Theoretically, the benefits of calcium channel blockers used a c u t e l y in myocardial infarction include relief of coronary artery spasm; in animals, improved collateral flow to ischemic areas; reduction of oxygen demand 20:5 May 1991
MYOCARDIAL INFARCTION Mitchell & Wheeler
by decreasing afterload, heart rate, and myocardial contractility; and reduction of calcium entry into cells, which may be related to ischemic cell injury and is of particular interest in patients who undergo reperfusion. The agents nifedipine, verapamil, and dihiazem each have different cardiovascular effects and should be considered separately. Although animal studies have been promising, clinical studies have not substantiated t h e m , and c a l c i u m c h a n n e l blockers are not advocated for routine use in the acute management of myocardial infarction.
Nifedipine There have been several clinical studies on the effect of nifedipine administration acutely in myocardial infarction; study characteristics are given (Table 3). In an early trial, Muller et a] found that nifedipine did not affect the progression of threatened to actual myocardial infarction, had no impact on infarct size, did not improve six-month mortality, and was associated with a significantly higher two-week mortality. 27 This increased mortality, however, may be attributed to no deaths in the placebo group at two weeks. In the Norwegian NifedipJne Multicenter Trial, Sirnes et a] found no effect on CK or six-week mortality. 28 The Trial of Early N i f e d i p i n e in A c u t e M y o c a r d i a l I n f a r c t i o n (the Trent trial) showed no improvement in one-month mortality. 29 Sixty-four percent of these patients had documented myocardial infarctions, and the drug was administered early, within four hours, to only 32% of the patients. In 1986, Branagan et al performed a much smaller study, but treatment was a d m i n i s t e r e d earlier. 3o In this trial, nifedipine had no impact on one-month mortality, CK, or the progression of threatened to actual myocardial infarction. The CK data, however, were complete in less than half the study population. Gottlieb et al studied the effects of larger nifedipine doses. 31 They demonstrated no statistically significant improvement in peak CK, mortality, or recurrent myocardial infarction but commented that a m u c h larger patient population might be necessary for statistical significance. Finally, Walker et al found no change 20:5 May 1991
in in-hospital mortality or infarct size by enzyme determination when nifedipine was given even earlier. 32
Verapamil Fewer studies have involved the use of verapami] acutely in myocardial infarction. In 1984, the Danish Muhicenter Group on Verapamil and Myocardial Infarction administered placebo or IV verapamil shortly after admission to 1,436 patients. 33 The time interval from onset of symptoms to initiation of treatment varied from within six hours in 422 patients to more than 24 hours in 107 patients. Verapamil was given in an initial dose of 0.1 mg/kg IV and 100 mg orally followed by 100 mg orally three times a day for six months. Treatment was stopped if myocardial infarction was excluded. The end points of the study were six- and 12m o n t h m o r t a l i t y and reinfarction rates. Verapamil was found to have no effect on any parameter, even in patients treated early. A small study by Bussman et al looked at infarct size reduction by v e r a p a m i l i n s t e a d of m o r t a l i t y data. 34 Fifty-four patients were randomized to receive placebo or verapamil 5 mg IV and then 5 to 10 mg/ hr by infusion for two days. They demonstrated a 30% reduction in infarct size by e n z y m e s in the verapamil group. This is the only clinical trial demonstrating benefit from the use of verapamil in the management of acute myocardial infarction.
Diltiazern Gibson et al demonstrated that diltiazem significantly reduced the reinfarction rate in the first 14 days in pat i e n t s w i t h n o n - Q wave infarctions. 3s In a larger trial, d i h i a z e m showed a slight but not significant benefit on mortality and reinfarction in patients followed 12 to 52 months after myocardial infarction. 36 Subgroup analysis demonstrated significant benefits in those patients with non-Q wave myocardial infarctions. Additional subgroup analysis suggested improvement in adverse cardiac events in patients without pulmonary congestion and worsening of mortality and reinfarction rates in patients with pulmonary congestion. In both studies, dihiazem was started late, at least 24 hours after infarction. Despite the large studies of secondary prevention by dihiazem, only one Annals of Emergency Medicine
small, preliminary clinical study of its acute use in myocardial infarction has been done to determine its effects on infarct size and mortality. 37 Thirty-two patients with acute myocardial i n f a r c t i o n c o m p l e t e d the study and received either placebo or dihiazem 10 mg IV over two minutes within six hours of symptoms, followed by 15 mg/hr for 72 hours and then 60 mg orally every six hours for three weeks. Infarct size was determined by radionuclide studies done on admission, at 48 hours, and at three weeks. CK data were available in most patients and showed no benefit from diltiazem. However, there was i m p r o v e m e n t in the ejection fraction and a decrease in the infarct defect in those treated with dihiazero. The study must be interpreted with caution because of the sample size. The c a l c i u m c h a n n e l blockers have been studied with great enthusiasm for their potential effects on myocardial salvage and mortality in acute myocardial infarction. It seems apparent from the trials that they are not useful in the acute management of myocardial ischemia or infarction. However, in secondary prevention and prophylaxis against recurrent ischemia, d i h i a z e m appears to have beneficial effects after non-Q wave infarction. Even more exciting is their potential use in the reduction of calciummediated ischemic injury after reperfusion. This, however, was not substantiated in a trial by Erbel et al, who aggressively managed 149 patients with acute myocardial infarction. 38 All patients received aspirin, IV streptokinase and heparin, intracoronary streptokinase, and coronary angioplasty if the lesion was more than 75% occluded. The c o n t r o l group r e c e i v e d placebo, and the treated group received nifedipine 20 mg sublingually and 0.2 mg infused into the occluded coronary artery, followed by 20 mg three times a day. Nifedipine was not shown to have a protective effect on reperfused myoeardium based on enzyme data, left ventricular function demonstrated by cineventriculography, or mortality.
13-BLOCKING AGENTS Of all the agents, f3-blockers have been studied the most extensively. The c l i n i c a l effects of early IV f3-blockade on acute myocardial in544/101
M Y O C A R D I A L INFARCTION Mitchell & Wheeler
TABLE 4. /V ~3-blockers in acute myocardial infarction No. of Patients Treated Placebo Total
Reference
Year Agent
Hjalmarson et a143 (Goteburg)
1981 Metoprolol
698
697
1,395
Yusuf et a142
1983 Atenolol
244
233
ICSG44
1984 Timolo[
73
Roberts et a[45
1984 Propranolol
134
mg
Initial Dose Time (hr)*
15t
(Within 48) 11.3 _+ 0.3
477
5~,
(Within 12) 5.0
71
144
1
(Within 4)
135
269
0.I kg
(Within 18) (Within 4):
The Golden Hours of the Myocardial Infarction: Nonthrombolytic Interventions Emergency care of patients with acute myocardial infarction requires active decision making to use agents that may improve morbidity and mortality. Thrombolysis remains the primary tool to accomplish this goal. Other pharmacologic agents, including lidocaine, nitrates, calcium channel blockers, f~-blockers, and aspirin, have been used acutely in myocardial infarction in the hopes of preventing death and salvaging myocardium. The decision to select one or all of these agents requires a knowledge of the clinical evidence of their efficacy and risk-to-benefit ratios. The clinical studies of the use of these agents acutely in the management of myocardial infarction are reviewed. [Mitchell JM, Wheeler WS: The golden hours of the myocardial infarction: Nonthrombolytic interventions. Ann Emerg Med May 1991;20:540-548.] INTRODUCTION Because of the reassessment of lidocaine, the advent of thrombolytic and aggressive reperfusion therapy, and newer data on the usefulness of other agents, especially aspirin and p-blockers, the management of acute myocardial infarction has changed significantly in the past decade. Previous management was directed at reduction of infarct extension and the prevention and treatment of arrhythmic deaths. This consisted mainly of bedrest, oxygen, pain relief, prophylactic antiarrhythmics, and treatment of complications. Now, in addition to previous directives, the goal in myocardial infarction therapy is preservation of myocardium in an attempt to improve mortality as well as postinfarction lifestyle and morbidity. Although reperfusion holds the most promise in myocardial salvage, studies continue to search for adjunct agents that may decrease myocardial oxygen demand as well as infarct size. Other agents studied in myocardial infarction management include prophylactic lidocaine, nitrates, calcium channel blockers, f~-blocking agents, and aspirin. This article presents an overview of the clinical studies of the use of these agents acutely in myocardial infarction and determines guidelines for their use. Trials from a literature search of the past seven years as well as older landmark studies are included.
Joyce M Mitchell, MD, FACEP* William S Wheeler, MD, FACCt Greenville, North Carolina From the Departments of Emergency Medicine* and Medicine,t East Carolina University School of Medicine/Pitt County Memorial Hospital, Greenville, North Carolina.
Received for publication March 12, 1990. Revision received October 12, 1990. Accepted for publication December 18, 1990. Presented at the Winter Symposium of the American College of Emergency Physicians in Tucson, Arizona, March 1990. Address for reprints: Joyce M Mitchell, MD, FACER Department of Emergency Medicine, East Carolina University School of Medicine/Pitt County Memorial Hospital, Greenville, North Carolina 27858-4354.
LIDOCAINE Initially synthesized and used as a local anesthetic in 1943, lidocaine demonstrated suppressive effects on ventricular premature beats (VPBs) during studies of the hemodynamic effects of its IV administration in the 1950s. 1 With the development of coronary care units in the 1960s, the prevention of ventricular fibrillation was advocated by Lown et al, 2 who also promoted the concept of warning arrhythmias that heralded the onset of ventricular fibrillation. Lidocaine was therefore administered when warning arrhythmias occurred. The theory of warning arrhythmias, however, was not supported in further studies. Ventricular fibrillation did not occur in all patients with warning arrhythmias and did occur in their absence, g-6 It was at this time that truly prophylactic use of lidocaine began. Lidocaine was administered to patients with suspected myocardial infarction before the recognition of ventricular ectopy or arrhythmias. The concept of prophylactic lidocaine is controversial. It has been adamantly advocated by some and highly questioned by others. The rationale
20:5 May 1991
Annals of Emergency Medicine
540/97
M Y O C A R D I A L INFARCTION Mitchell & Wheeler
TABLE 1. Lidocaine in acute myocardial infarction
Reference
Year
Setting
Lie et al lo
1974
Hospital
Barnaby et alit Koster and Dunningr2
1983 1985
Hospital Prehospital
Dunn et a113
1985
Varied
No. of Patients Treated Placebo Total
Route
Dose (mg)
Infusion (mg/min)
Treatment or Study Period (br)
107
105
212
IV
100
3
48
111 2,987
... 3,037
111 6,024
IV IM
75 400
4.-~.2
48 1
207
195
402
IM IV
300 100
1
End Points VF, VPBs, mortality VE VT, VPBs VE mortality VE mortality
VF, venbieular fibrillation; VPBs, ventbcular premature beats; ~ ventrieular lachycardia.
for its use should be based on four basic assumptions, which are disCussed: 1) primary ventricular fibrillation is common in myocardial infarction, 2) the occurrence of ventricular fibrillation increases mortality, 3] lidocaine prevents p r i m a r y ventricular fibrillation and improves mortality, and 4) the benefits of lidocaine outweigh its adverse effects. Based on the clinical trials reported, the use of prophylactic lidocaine in all patients with suspected myocardial infarction is not supported. 7 First, studies have demonstrated a 3% to 10% in-hospital occurrence of primary ventricular fibrillation in association with m y o c a r d i a l infarction. s-lo Many sudden deaths occur outside of the hospital, and the incidence of ventricular fibrillation is inversely related to the time of onset of chest pain. lo Second, this has been suggested by several studies of in-hospital mortality of patients with primary ventricular fibrillation. An average of 19% of those with primary ventricular fibrillation died compared with an average of 8% in patients without primary ventricular fibrillation. 1 These n u m b e r s do not i n c l u d e p a t i e n t s with secondary ventricular fibrillation associated with congestive heart failure. This suggests that prevention of ventricular fibrillation would have a favorable effect on outcome in patients with myocardial infarction. Third, animal studies have shown mixed results on the effects of lidocaine in the suppression of ventricular a r r h y t h m i a s . Several clinical studies have assessed the efficacy of prophylactic lidocaine in preventing ventricular fibrillation in acute myocardial infarction. The characteristics of these trials are outlined (Table 1). Lie et al studied 212 patients with documented myocardial infarction. H 98/541
P a t i e n t s were excluded from the study if they were more than 70 years old or had congestive heart failure, shock, complete atrioventricular block, bradycardia, or persistent ventricular tachycardia or ventricular fibrillation on admission. None of the treated patients developed ventricular fibrillation. Of the placebo group, nine developed ventricular fibrillation; this was a statistically significant difference and supported the ass u m p t i o n that lidocaine prevents ventricular fibrillation. All but one of the nine were successfully defibrillated. In four of nine patients who developed ventricular fibrillation warning arrhythmias did not occur, suggesting that warning arrhythmias were not helpful in the decision to administer lidocaine. The mortality rates in both groups were the same. Barnaby et al treated all patients in their study with lidocaine within 24 hours of the onset of acute myocardial infarction. 1~ Exclusion criteria were similar to those in Lie et al's study. No patients developed ventricular fibrillation. Thirty-two percent had warning arrhythmias, and 4% had n o n s u s t a i n e d ventricular tachycardia. Four developed hypotension, and one developed bradycardia. Thirty percent of patients suffered symptoms of lidocaine toxicity, none of which was major. Despite the fact that this was an uncontrolled study, the investigators made the conclusion that prophylactic lidocaine was efficacious in suppression of ventricular fibrillation and that its use was particularly important outside the coronary care unit where close monitoring and rapid defibrillation were less available. In 1985, Koster and Dunning studied the use of prophylactic IM lidocaine in prehospital-care patients with suspected myocardial infarcAnnals of Emergency Medicine
tion.13 All patients were admitted to the study based on symptoms regardless of age, with exclusions for severe congestive heart failure, pretreatment with lidocaine, and resuscitation from ventricular fibrillation or by a physician's judgment. Of the patients included in the study, myocardial infarction was documented in 1,935. The IM route was selected because of its ease of use in the prehospital phase; it had been demonstrated previously to produce therapeutic serum levels 15 minutes after injection. Ventricular fibrillation was treated by defibrillation. The study period was one hour. During this time, eight of the treated and 17 of the untreated patients developed ventricular fibrillation (P = NS). However, in the last 45 minutes of the study, two of the lidocaine-treated and 12 of the untreated patients developed ventricular fibrillation, which was statistically significant. Ventricular fib r i l l a t i o n was d e f i b r i l l a t e d succ e s s f u l l y in all b u t one of t h e patients, in whom it was unrecognized and untreated for 11 minutes. The m o r t a l i t y rates in patients who developed ventricular fibrillation were virtually the same in both groups. More patients treated with ]idocaine developed asystole, but asystolic deaths in both groups were the same. The total mortality for both groups was also essentially the same. The authors concluded that if ventricular fibrillation had not been treated, by defibrillation, the administ r a t i o n of l i d o c a i n e w o u l d have caused a 31% reduction in mortality. Therefore, prophylactic IM ]idocaine would be useful in the setting in which potential sudden death is possible and immediate defibrillation is not available. Finally, Dunn et al studied the effects of lidocaine in patients with 20:5 May 1991
MYOCARDIAL INFARCTION Mitchell & Wheeler
TABLE 2. IV nitroglycerin in acute myocardial infarction
Reference Bussman et al2o
No. of Patients Year Treated Placebo Total Time*
Duration of Study (hr)
1981
31
29
60
Varied
48
Jaffe et a117 Flaherty et al2~
1983 1983
43 56
42 48
85 104
Within 10 hr Within 12 hr
? 24 Varied
Korewicki et a122
1984
39
38
77
Within 8 hr
48
End Points Infarct size (OK, CK-M8) infarct size (CK) Infarct extension, new heart failure, arrhythmias, infarct size, mortality Infarct size (OK), hemodynamics
*Onsel of symptoms to initiation of therapy
suspected myocardial infarction. 14 These patients were treated in the prehospital phase (78%), in the emergency department (18%), or after admission (4%) with similar exclusion criteria as previous studies. Of the patients studied, 364 had either myocardial infarction or acute coronary insufficiency. During the study period, three untreated patients developed v e n t r i c u l a r fibrillation (P = NS), and three lidocaine-treated patients developed sustained ventricular tachycardia (P = NS). More patients treated with lidocaine developed 2:1 atrioventricular block or asystole with death, but this.was not statistically significant. The mortality outside the study period was the same in both groups. Although the authors stated that their study may have been too small to create statistically significant differences in the two groups, they concluded that prophylactic lidocaine should not be advocated as the routine practice in acute myocardial infarction. Fourth, Rademaker et al studied adverse side effects in patients who received prophylactic lidocaine (100 mg IV followed by a 3 mg/min infusion) compared with those who did not. is T h e y f o u n d t h a t lidocaine caused significantly more side effects, albeit minor in m a n y cases, and that they were more common in patients without myocardial infarction. Five of 145 patients suffered life-threatening side effects, including seizures, coma with respiratory arrest, and persistent severe sinus bradycardia. They concluded that the adverse effects of lidocaine may negate its routine prophylactic use. Yusuf et al pooled the results of 11 randomized trials of 8,527 patients, which showed that lidocaine reduced 20:5 May 1991
the risk of ventricular fibrillation by 36% with a c o n c o m i t a n t but only borderline statistically significant doubling of fatal asystole. 16 They concluded that the routine use of antiarrhythmics in asymptomatic patients was not supported by pooled data. These studies suggest that lidocaine is effective in preventing primary ventricular fibrillation, but the mortality in treated versus untreated patients was the same. 11d4 Recently, Hines et al performed a meta-analysis of the studies on prophylactic lidocaine, supporting this finding. 7 They also showed that monitored patients with uncomplicated myocardial infarction were more likely to die during the treatment period if they received the drug. Despite potential psychological and physical consequences of resuscitation from ventricular fibrillation, the adverse effects of lidocaine probably outweigh its routine use due to the negative mortality effect and the potential of life-threatening side effects in patients who are suspected but later disproved of suffering acute myocardial infarction. The conclusion of Koster and Dunning is probably a good guideline for the use of prophylactic lidocaine: When defibrillation is unavailable and potential ventricular fibrillation is possible, prophylactic lidocaine may improve mortality. 13 With the development of emergency medical technician-defibrillation status, the need for this in the prehospital phase of management of patients with suspected myocardial infarction might be eliminated.
NITRATES Nitrates have been used since the Annals of Emergency Medicine
latter part of the 1800s for chest pain syndromes but were previously considered inappropriate for use in acute myocardial infarction because of potential side effects. These adverse effects include hypotension and reflex tachycardia, which in turn would increase myocardial oxygen consumption as well as the i d i o s y n c r a t i c b r a d y c a r d i c / h y p o t e n s i v e response seen in some patients. 17 Theoretically, however, nitrates should have beneficial effects because of two main actions. First, preload and afterload reductions result in decreased left ventricular filling pressures, thus decreasing myocardial oxygen demands. In experimental studies, nitrates have been shown during acute coronary occlusion to increase collateral blood flow to ischemic areas with a secondary potential benefit on infarct size. is There have been several trials addressing the effects of nitrates on myocardial infarction. Current recommendations advocate the use of nitrates in selected patients. In 1976, Awan et al administered 0.4 mg nitroglycerin sublingually to 11 patients with documented acute m y o c a r d i a l infarction.I9 Patients were not included in this small study if they were hypotensive or demonstrated conduction disturbances, persistent arrhythmias, heart failure, or pericarditis. Infarct size was determined by precordial mapping of ST segments and was found to be decreased by sublingual nitroglycerin. This led to further studies using IV nitroglycerin because it was more titratable and side effects could be avoided. The characteristics of these studies are outlined (Table 2). Bussman et al studied patients with acute myocardial infarction documented by clinical, ECG, and enzyme criteria. ~° All patients received SwanGanz catheterization and were included in the study only if pulmonary arterial diastolic or capillary pressures were more than 15 m m Hg. Infarct size was determined by creatine kinase (CK), CK-MB, and peaks of each. The groups were also subgrouped into early (within eight hours; mean, 4.5 hours) and late (after eight hours; mean, 12.8 hours) treatment. The results demonstrated significant reduction in infarct size with nitroglycerin in both early and late treatment groups, although early treatment was associated with better 542/99
M Y O C A R D I A L INFARCTION Mitchell & Wheeler
TABLE 3. Nifedipme in acute myocardial infarction No. of Patients Initial Dose Treated Placebo Total mg Route Time (hr)*
Reference
Year
Muller et a127
1984
82
89
171
20
0ral
Sirnes et a128
1984
112
115
227
10
0ral
Wilcox et a129 (Trent trial)
1986
2240
' 2,251
4,491
10
Sublingual
Branagan et al3o
1986
46
52
98
10
Sublingual
Gottlieb et a131
1988
64
68
132
10
Walker et a132
1988
217
217
434
10
?
Sublingual
Subsequent Doses
Duration
End Points
(Within 6) 4.6+1 (Within 12) 5.5 +_ 2.9 (Within 4): 32% (8): 68% (12): 81% (Within 6) 3.3 z 0.2
Every 4 hr
14 days
Threatened MIAMI, infarct size (CK-MB), mortality Infarct size (CK-MB), mortality Mortality
(Within 12) 8.0% = 02
Repeat every hr for 2, 6 weeks then 10-30 mg every 6 hr Every 4 hr for 24 hr orally, 48 hours every 4 hr for 24 hr
(Within 6) 2.3
Repeat 10 m, 5 times daily 6 weeks for 2 days, 4 times daily Repeat 4 hr every 6 hr Approximately 28 days Repeat 4 hr, orally every 6 hr
3 days
Infarct size (CK-MB), threatened MIAMI, mortality Infarct size (CK, echocardiogram, nuclear scans) Infarct size (CK, CK-MB, others)
*Onset of symptoms to first dose MI, myocardial infarction. (), inclusion criteria
results. The study group, however, was small. Jaffe et al studied the effect and safety of IV nitroglycerin in patients with documented myocardial infarction. 17 Patients were excluded for cardiogenic shock, severe heart failure with tachycardia, and severe hypertension. Before r a n d o m i z a t i o n , the patients were classified according to site of infarct. Infarct size was measured by CK gram equivalents per meter squared. There was a borderline significant reduction in infarct size for all patients. Nitroglycerin showed a significant reduction in infarct size among patients with inferior myocardial infarctions, a positive but not statistically significant trend in subendocardia] myocardial infarctions, and no change in anterior wall myocardial infarctions. M o r p h i n e r e q u i r e m e n t s were the same in patients regardless of treatment or infarct location. Six patients developed transient laypotension w i t h o u t deleterious effects. T h e y concluded that IV nitroglycerin was safe and effective in the reduction of infarct size in patients with inferior myocardial infarctions. Flaherty et al studied the effects of IV nitroglycerin on the clinical parameters of infarct extension, new heart failure, ventricular arrhythmias, and early death as well as laboratory parameters of infarct size (thallium perfusion scans, gated cardiac blood pool scans, two-dimensional echocardiography, precordial 100/543
E C G m a p p i n g , and serial CK). 21 N i n e t y - s e v e n p a t i e n t s had docum e n t e d myocardial infarction. Patients were excluded for age of more than 75 years, hypotension, bradycardia, and severe hypertension. At the end of their study, no difference in clinical or laboratory parameters could be determined. By retrospective subgrouping of patients into groups treated less or more than ten hours after onset of symptoms, they were able to determine some difference. Individually considered, nitroglycerin did not affect the clinical complications of myocardial infarction, but early treatment with nitroglycerin significantly reduced the combination of death, infarct extension, heart failure, and ventricular arrhythmias. The three-month mortality was improved in the early nitrog l y c e r i n g r o u p (P = NS). CK p a r a m e t e r s were not affected, but there appeared to be improvement in ejection fraction measurements with early nitroglycerin treatment. Flaherty et al also recommended that the data be interpreted with caution because of the size and retrospective subgroup analysis and proposed that recommended routine nitroglycerin in acute myocardial infarction await larger trials. 21 Korewicki et al demonstrated reduction in CK parameters if the drug was administered within eight hours. 22 Other studies have refuted the preferential reduction of infarct size in inferior myocardial.infarcAnnals of Emergency Medicine
tions demonstrated by Jaffe, 23 but two studies demonstrated improvement in patients with anterior myocardial infarctions.24, 25 It is difficult to m a k e definitive conclusions about the routine use of nitrates acutely in myocardial infarction based on the data of individual studies. Pooling of results suggests that IV nitrates improve m o r t a l i t y and m a y reduce infarct size.t6,18, 26 This positive trend and the fact that IV nitroglycerin is relatively safe, with adverse effects that are usually easily managed, suggest that nitrates should be used acutely in myocardial infarction in selected patients, especially those w i t h p e r s i s t e n t chest pain. After screening patients who may be susceptible to its hypotensive effects, those who are hypovolemic or may require high filling pressures to maintain cardiac output such as right ventricular infarction, IV nitrog l y c e r i n can r e a s o n a b l y be used safely. The advocation of routine use, however, should probably await larger studies. CALCIUM CHANNEL BLOCKERS
Since their introduction, calcium channel blockers have been used for a variety of cardiovascular diseases. Theoretically, the benefits of calcium channel blockers used a c u t e l y in myocardial infarction include relief of coronary artery spasm; in animals, improved collateral flow to ischemic areas; reduction of oxygen demand 20:5 May 1991
MYOCARDIAL INFARCTION Mitchell & Wheeler
by decreasing afterload, heart rate, and myocardial contractility; and reduction of calcium entry into cells, which may be related to ischemic cell injury and is of particular interest in patients who undergo reperfusion. The agents nifedipine, verapamil, and dihiazem each have different cardiovascular effects and should be considered separately. Although animal studies have been promising, clinical studies have not substantiated t h e m , and c a l c i u m c h a n n e l blockers are not advocated for routine use in the acute management of myocardial infarction.
Nifedipine There have been several clinical studies on the effect of nifedipine administration acutely in myocardial infarction; study characteristics are given (Table 3). In an early trial, Muller et a] found that nifedipine did not affect the progression of threatened to actual myocardial infarction, had no impact on infarct size, did not improve six-month mortality, and was associated with a significantly higher two-week mortality. 27 This increased mortality, however, may be attributed to no deaths in the placebo group at two weeks. In the Norwegian NifedipJne Multicenter Trial, Sirnes et a] found no effect on CK or six-week mortality. 28 The Trial of Early N i f e d i p i n e in A c u t e M y o c a r d i a l I n f a r c t i o n (the Trent trial) showed no improvement in one-month mortality. 29 Sixty-four percent of these patients had documented myocardial infarctions, and the drug was administered early, within four hours, to only 32% of the patients. In 1986, Branagan et al performed a much smaller study, but treatment was a d m i n i s t e r e d earlier. 3o In this trial, nifedipine had no impact on one-month mortality, CK, or the progression of threatened to actual myocardial infarction. The CK data, however, were complete in less than half the study population. Gottlieb et al studied the effects of larger nifedipine doses. 31 They demonstrated no statistically significant improvement in peak CK, mortality, or recurrent myocardial infarction but commented that a m u c h larger patient population might be necessary for statistical significance. Finally, Walker et al found no change 20:5 May 1991
in in-hospital mortality or infarct size by enzyme determination when nifedipine was given even earlier. 32
Verapamil Fewer studies have involved the use of verapami] acutely in myocardial infarction. In 1984, the Danish Muhicenter Group on Verapamil and Myocardial Infarction administered placebo or IV verapamil shortly after admission to 1,436 patients. 33 The time interval from onset of symptoms to initiation of treatment varied from within six hours in 422 patients to more than 24 hours in 107 patients. Verapamil was given in an initial dose of 0.1 mg/kg IV and 100 mg orally followed by 100 mg orally three times a day for six months. Treatment was stopped if myocardial infarction was excluded. The end points of the study were six- and 12m o n t h m o r t a l i t y and reinfarction rates. Verapamil was found to have no effect on any parameter, even in patients treated early. A small study by Bussman et al looked at infarct size reduction by v e r a p a m i l i n s t e a d of m o r t a l i t y data. 34 Fifty-four patients were randomized to receive placebo or verapamil 5 mg IV and then 5 to 10 mg/ hr by infusion for two days. They demonstrated a 30% reduction in infarct size by e n z y m e s in the verapamil group. This is the only clinical trial demonstrating benefit from the use of verapamil in the management of acute myocardial infarction.
Diltiazern Gibson et al demonstrated that diltiazem significantly reduced the reinfarction rate in the first 14 days in pat i e n t s w i t h n o n - Q wave infarctions. 3s In a larger trial, d i h i a z e m showed a slight but not significant benefit on mortality and reinfarction in patients followed 12 to 52 months after myocardial infarction. 36 Subgroup analysis demonstrated significant benefits in those patients with non-Q wave myocardial infarctions. Additional subgroup analysis suggested improvement in adverse cardiac events in patients without pulmonary congestion and worsening of mortality and reinfarction rates in patients with pulmonary congestion. In both studies, dihiazem was started late, at least 24 hours after infarction. Despite the large studies of secondary prevention by dihiazem, only one Annals of Emergency Medicine
small, preliminary clinical study of its acute use in myocardial infarction has been done to determine its effects on infarct size and mortality. 37 Thirty-two patients with acute myocardial i n f a r c t i o n c o m p l e t e d the study and received either placebo or dihiazem 10 mg IV over two minutes within six hours of symptoms, followed by 15 mg/hr for 72 hours and then 60 mg orally every six hours for three weeks. Infarct size was determined by radionuclide studies done on admission, at 48 hours, and at three weeks. CK data were available in most patients and showed no benefit from diltiazem. However, there was i m p r o v e m e n t in the ejection fraction and a decrease in the infarct defect in those treated with dihiazero. The study must be interpreted with caution because of the sample size. The c a l c i u m c h a n n e l blockers have been studied with great enthusiasm for their potential effects on myocardial salvage and mortality in acute myocardial infarction. It seems apparent from the trials that they are not useful in the acute management of myocardial ischemia or infarction. However, in secondary prevention and prophylaxis against recurrent ischemia, d i h i a z e m appears to have beneficial effects after non-Q wave infarction. Even more exciting is their potential use in the reduction of calciummediated ischemic injury after reperfusion. This, however, was not substantiated in a trial by Erbel et al, who aggressively managed 149 patients with acute myocardial infarction. 38 All patients received aspirin, IV streptokinase and heparin, intracoronary streptokinase, and coronary angioplasty if the lesion was more than 75% occluded. The c o n t r o l group r e c e i v e d placebo, and the treated group received nifedipine 20 mg sublingually and 0.2 mg infused into the occluded coronary artery, followed by 20 mg three times a day. Nifedipine was not shown to have a protective effect on reperfused myoeardium based on enzyme data, left ventricular function demonstrated by cineventriculography, or mortality.
13-BLOCKING AGENTS Of all the agents, f3-blockers have been studied the most extensively. The c l i n i c a l effects of early IV f3-blockade on acute myocardial in544/101
M Y O C A R D I A L INFARCTION Mitchell & Wheeler
TABLE 4. /V ~3-blockers in acute myocardial infarction No. of Patients Treated Placebo Total
Reference
Year Agent
Hjalmarson et a143 (Goteburg)
1981 Metoprolol
698
697
1,395
Yusuf et a142
1983 Atenolol
244
233
ICSG44
1984 Timolo[
73
Roberts et a[45
1984 Propranolol
134
mg
Initial Dose Time (hr)*
15t
(Within 48) 11.3 _+ 0.3
477
5~,
(Within 12) 5.0
71
144
1
(Within 4)
135
269
0.I kg
(Within 18) (Within 4):
